Treatment Of Arterial Hypertension Research Articles

Efficacy and Organoprotection of Triple Combinations in the Treatment of Arterial Hypertension

Efficacy and Organoprotection of Triple Combinations in the Treatment of Arterial Hypertension

Retracted: Advances in the Study of Inhaled Formulations for the Treatment of Pulmonary Arterial Hypertension

Retracted: Advances in the Study of Inhaled Formulations for the Treatment of Pulmonary Arterial Hypertension

Intratracheally Administered Peptide-Modified Lipid Admixture Containing Fasudil and/or DETA NONOate Ameliorates Various Pathologies of Pulmonary Arterial Hypertension.

This study examined the therapeutic potential of a combination therapy using fasudil, a Rho-kinase inhibitor, and DETA NONOate (DN), a nitric oxide donor, delivered as a lipid admixture modified with a cyclic homing peptide known as CAR (CAR-lipid mixture) for the treatment of pulmonary arterial hypertension (PAH). CAR-lipid mixtures were initially prepared via a thin-film hydration method and then combined with fasudil, DN, or a mixture of both. The therapeutic efficacy of this drug-laden lipid mixture was evaluated in a Sugen/Hypoxia (Su/Hx) rat model of PAH by measuring RV systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), Fulton indices, and assessing right ventricular (RV) functions, as well as evaluating pulmonary vascular morphology. Rats that received no treatment exhibited increases in RVSP, mPAP, Fulton indices, and changes in RV functional parameters. However, the treatment with the CAR-lipid mixture containing either fasudil or DN or a combination of both led to a decline in mPAP, RVSP, and Fulton indices compared to saline-treated rats. Similarly, rats that received these treatments showed concurrent improvement in various echocardiographic parameters such as pulmonary acceleration time (PAT), tricuspid annular plane systolic excursion (TAPSE), and ventricular free wall thickness (RVFWT). A significant decrease in the wall thickness of pulmonary arteries larger than 100 µm was observed with the combination therapy. The findings reveal that fasudil, DN, and their combination in a CAR-modified lipid mixture improved pulmonary hemodynamics, RV functions, and pathological alterations in the pulmonary vasculature. This study underscores the potential of combination therapy and targeted drug delivery in PAH treatment, laying the groundwork for future investigations into the optimization of these treatments, their long-term safety and efficacy, and the underlying mechanism of action of the proposed therapy.

The efficacy of the treat-repair-treat strategy for severe pulmonary arterial hypertension associated with congenital heart disease: a meta-analysis

BackgroundThis meta-analysis was conducted to evaluate the efficacy of the treat-repair-treat (TRT) strategy in the treatment of severe pulmonary arterial hypertension with congenital heart disease (PAH-CHD).MethodsPubMed, EMBASE, Cochrane and Web of Science online databases were searched by two independent investigators for studies that used the TRT strategy for PAH-CHD, and the retrieved studies were reviewed by a third investigator. The main outcomes were pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), and transcutaneous oxygen saturation (SpO2). The changes were compared between follow-up and baseline. Stata version 14.0 was used for data analysis. A random-effects model was selected for meta-analysis. Subgroup analysis and meta-regression were used to find the source of heterogeneity.ResultsA total of 335 patients from 9 single-arm studies were included. Meta-analysis showed significant reductions in PAP and PVR and improvements in 6MWD and SpO2 (PAP: SMD -2.73 95% CI -2.97, − 2.50 p = < 0.001; PVR: SMD -1.27 95% CI -1.53, − 1.02 p = < 0.001; 6MWD: SMD 1.88 95% CI 1.49, 2.27 p = < 0.001; SpO2: SMD 3.72 95% CI 3.13, 4.32 p = < 0.001). Subgroup analysis showed that younger patients had better efficacy, and the change in SpO2 was an indication for patient selection. The combined mortality rate was 5% at follow-up.ConclusionsIn this meta-analysis, we demonstrated that the TRT strategy may have positive effects on haemodynamics and cardiac function in patients with severe PAH-CHD at short-term follow-up. Our analysis suggests that changes in age and SpO2 may be related to patient prognosis.Trial registrationThe protocol was registered on the PROSPERO website with the registration number CRD42022366552. The relevant registration information can be obtained from the website https://www.crd.york.ac.uk/prospero/#searchadvanced.

From Fish Physiology to Human Disease: The Discovery of the NCC, NKCC2, and the Cation-Coupled Chloride Cotransporters.

The renal Na-K-2Cl and Na-Cl cotransporters are the major salt reabsorption pathways in the thick ascending limb of Henle loop and the distal convoluted tubule, respectively. These transporters are the target of the loop and thiazide type diuretics extensively used in the world for the treatment of edematous states and arterial hypertension. The diuretics appeared in the market many years before the salt transport systems were discovered. The evolving of the knowledge and the cloning of the genes encoding the Na-K-2Cl and Na-Cl cotransporters were possible thanks to the study of marine species. This work presents the history of how we came to know the mechanisms for the loop and thiazide type diuretics actions, the use of marine species in the cloning process of these cotransporters and therefore in the whole solute carrier cotransproters 12 (SLC12) family of electroneutral cation chloride cotransporters, and the disease associated with each member of the family.

Efficacy and safety aspects of renal denervation in treatment of arterial hypertension: a systematic review and meta-analysis

Abstract Introduction Current guidelines for the management of arterial hypertension 2018 of European Society for Cardiology (ESC) do not recommend use of renal denervation (RDN) (as device-based therapy) for treatment of hypertension except as part of clinical studies. However, in the meantime several randomized sham-controlled clinical trials were designed using second generation radiofrequency (RF) (SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED), ultrasound (RADIANCE-HTN SOLO, RADIANCE-HTN TRIO) or alcohol-mediated renal denervation (TARGET BP-OFF) devices. We aimed to perform a comprehensive meta-analysis from all published and unpublished randomized, sham-controlled clinical trials which explored the effects of renal denervation on blood pressure across different devices. Methods We searched MEDLINE and Embase via OVID@ for eligible trials. Of note, we also included unpublished data from the SPYRAL-ON Extension and TARGET BP OFF trials. Pooling the data from all studies, we explored the efficacy (ambulatory and office systolic and diastolic BP) and safety (all cause death, vascular complication, renal artery stenosis &amp;gt;70%, hypertensive crisis) of RDN. Results Analysis included 9 eligible trials (i.e. SYMPLICITY HTN-3, ReSET, SPYRAL HTN OFF MED, Desch et al., RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, RADIANCE, TARGET BP OFF, SPYRAL HTN ON MED extension) comprising 2,091 patients (Table 1). RDN reduced ambulatory systolic (-3.10 mmHg, 95% CI -4.22, -1.97, p&amp;lt;0.00001) and office systolic (-5.15 mmHg, 95% CI -6.65, -3.66, p&amp;lt;0.00001) BP and ambulatory diastolic (-1.58 mmHg, 95% CI -2.54, -0.63, p=0.001) and office diastolic (-2.74 mmHg, 95% CI -3.65, -1.83, p&amp;lt;0.00001) BP compared with sham groups. There was no difference concerning ambulatory SBP reduction between trials with ON medication design (-2.94 mmHg, p&amp;lt;0.0001) and those with OFF medication design (-3.37 mmHg, p&amp;lt;0.0001) (p for interaction 0.69). Similarly, office SBP reduction was comparable between trials with (-4.38 mmHg, p&amp;lt;0.0001) and without concomitant antihypertensive drugs prescription (-6.27 mmHg, p&amp;lt;0.00001) (p for interaction 0.22). The rate of vascular complications (OR 1.21, 95% CI 0.28, 5.25, p=0.80), renal artery stenosis (OR 1.50, 95% CI 0.06, 36.97, p=0.80), hypertensive crisis (OR 1.39, 95% CI 0.50, 3.92, p=0.53) and all cause death (OR 0.52, 95% CI 0.10, 2.83, p=0.45) was not different between treatment and sham groups. Conclusions RDN is associated with clinically significant reductions in ambulatory and office SBP as compared with sham in the presence and absence of antihypertensive medication. The procedure use was not associated with an excess in safety events compared with sham group.

Development of KER-012, a modified ActRIIB ligand trap, for the treatment of pulmonary arterial hypertension

Abstract Background Pulmonary Arterial Hypertension (PAH) is a debilitating disorder characterized by elevated pulmonary vascular resistance (PVR) due to severe constriction obliteration of pulmonary vessels (Tielemans 2019). The pathology of PAH is driven by endothelial dysfunction and vascular remodeling that leads to increased wall thickening and resistance to blood flow. Dysregulated TGF-β, specifically SMAD signaling, is a key molecular defect in proliferative thickening of pulmonary arterioles in PAH leading to increased arterial pressure and compensatory right ventricular hypertrophy, ultimately resulting in decompensated right heart failure. Increased levels of activin A, a TGF-β superfamily ligand, have been found in PAH patients, and in the lungs of hypoxia-induced pulmonary hypertensive mice (Yndestad 2009). KER-012 is an investigational modified ActRIIB ligand trap designed to bind and inhibit activin A, activin B, GDF8 and GDF11 to maximally inhibit SMAD2/3 (pro proliferative), while permitting SMAD1/5/9 (anti-proliferative) signaling. This profile is expected to rebalance defective SMAD signaling in PAH and potentially delay or reverse disease progression. Aim To evaluate safety and tolerability of KER-012 in healthy post-menopausal women (PMW) and present the planned design of a Phase 2 trial in participants with PAH. Methods A two-part Phase 1 study has been conducted with KER-012 in healthy PMW. Participants received either placebo or a single dose of KER-012 ranging between 0.75 and 5.0 mg/kg in Part 1 or multiple doses between 0.75 and 4.5 mg/kg in Part 2 subcutaneously once every 4 weeks over a 12-week period. Safety, PK and biomarkers of activin target engagement were assessed. Results KER-012 was generally well tolerated at dose levels up to 5 mg/kg as a single dose and at dose levels up to 4.5 mg/kg administered Q4W for a total of 3 doses (Table 1). Maximal target engagement of KER-012, as demonstrated by changes in biomarkers of activin inhibition, namely follicle stimulating hormone (FSH) and bone specific alkaline phosphatase (BSAP), was observed in this study. As previous studies with activin receptor type II ligand traps have shown a potentially dose-limiting increase in erythropoiesis, changes in red blood cells (RBC) were closely monitored in this study. KER-012 did not elicit any changes in hemoglobin or RBC count in the Phase 1 study (Figure 1). Summary KER-012 was generally well tolerated in healthy participants. The observed biomarker changes are consistent with inhibition of activins, suggestive of a balance shift in favor of signaling via the anti-proliferative SMAD 1/5/9 pathway. Based on this mechanism, administration of KER-012 could potentially result in reverse vascular remodeling and clinical cardiopulmonary improvements in patients with PAH, without targeting erythropoietic pathways. Given this profile, KER-012 is being advanced for development in patients with PAH in an upcoming Ph2 clinical trial (Figure 2).

Efficacy comparison of prostacyclin analogue and prostacyclin receptor agonist as third line treatment for pulmonary arterial hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive disease characterized by small pulmonary arteries remodeling that leads to increased pulmonary vascular resistance, dyspnea, fatigue, right heart failure and ultimately death. Prostacyclin analogue drugs, such as epoprostenol or treprostinil, have a vasodilator, antiproliferative and immunomodulatory effect, representing established therapies for cases of severe PAH. Both these drugs improve exercise capacity, functional class and hemodynamic parameters, while epoprostenol also improves survival among patients with PAH. Despite these therapeutic benefits, these treatments need parenteral administration. Recently, the approval of selexipag, an oral selective prostacyclin receptor agonist, may represent a possible alternative option in some PAH patients. Methods Patients with PAH treated as third line therapy with epoprostenol, treprostinil or selexipag, on top of inhibitor of type 5 phosphodiesterases and endothelin-1 receptor antagonists, referred to our center from February 1995 to December 2021 were retrospectively included. All patients noninvasive [6 minutes walking distance (6MWD)] and invasive [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), right atrial pressure (RAP) and mixed venous oxygen saturation (SvO2)] parameters were first collected at the baseline right heart catheterization (prior to the beginning of prostacyclin treatment) and then 3-4 months after the beginning of third line therapy. The absolute improvements in these parameters were compared with Dunn’s test. Data are expressed as median (interquartile range). Results 153 PAH patients treated as third line therapy with epoprostenol, treprostenil and selexipag were included (44, 73, 36 patients respectively). At 3 to 4 months after the beginning of the third line therapy, absolute improvements in the different parameters are shown in Figure 1. Conclusions In our study population, epoprostenol, treprostenil and selexipag improve both exercise capacity and haemodynamic parameters in PAH patients when used as third line therapy, with the highest efficacy in the first group and, possibly, the lowest efficacy in the latter. These results confirm the beneficial role of these drugs in PAH patients and may suggest a possible favorable role for selexipag in the management of PAH patients with a less severe disease reserving a more invasive treatment strategy with parenteral prostanoids in patients with a higher risk disease.Figure 1

Superiority of CS585 as a selective prostacyclin receptor agonist in prevention of thrombosis

Abstract Background A major challenge with development of new targets for antithrombotic treatment is the sustained effect on the platelet and the target selectivity. While increasing cAMP in the platelet through activation of the prostacyclin (IP) receptor represents a viable antiplatelet target for prevention of thrombosis, current IP receptor agonists lack stability and selectivity. Development of a selective IP receptor agonist that is stable in the blood and selective for the IP receptor would represent a new approach for prevention of platelet activation and thrombosis in the blood and expand the utility of IP receptor agonists which are currently used for the treatment of pulmonary arterial hypertension (PAH). Purpose Develop an IV and oral IP receptor agonist, CS585, with sustained activity in vivo in the blood and eliminating the off-target effects observed with other IP agonists not having selective activation of the IP receptor. These characteristics would make CS585 an attractive new therapeutic approach for limiting platelet activation and thrombosis. Methods We assessed platelet activation and thrombosis in human blood ex vivo and mouse models in vivo. For mouse models, platelets and fibrin were labelled and accumulation at the site of injury was measured using intravital microscopy. Thrombosis in the vessel was assessed in the laser-induced cremaster thrombosis assay. Selectivity was assessed in human blood pharmacologically using prostaglandin receptor inhibitors and in mouse with an IP receptor knockout mouse. Flow cytometry, aggregometry, and western blot techniques were used to assess selectivity. Results IV and oral administration of CS585 resulted in sustained inhibited clot formation and fibrin formation at the site of injury in the laser-induced cremaster arteriole thrombosis assay in wild-type mice but was unable to alter platelet function in IP knockout mice. CS585 inhibition of platelet activation was fully prevented in platelets from IP knockout mice as assessed by flow cytometry (integrin activation and granule secretion) and by VASP phosphorylation. Inhibition of human platelet activation by CS585 was inhibited by pharmacological inhibition of the IP receptor, but not by inhibition of the DP1, EP2, or EP4 receptors as assessed by aggregation, flow cytometry, and VASP phosphorylation. Conclusions We have shown for the first time that CS585, a novel IP receptor agonist, not only inhibits platelet activation and clot formation, but gives sustained inhibition through multiple routes of administration in an in vivo mouse model of thrombosis. Importantly, the challenge in selectivity observed with other IP receptor agonists is not observed with CS585 supporting its development for a number of diseases in the cardiovascular system including thrombosis, VTE, secondary prevention after MI and stroke, and PAH.CS585 inhibition of thrombosis in vivoCS585 selectively signals through IP

The effect of amiodarone on the spectral parameters of heart rate variability in patients with various forms of atrial fibrillation

In this study, spectral parameters in patients with various forms of atrial fibrillation and the effect of the class III antiarrhythmic drug amiodarone on these parameters were studied. The use of spectral analysis of heart rate variability (hereinafter referred to as HRV) when choosing a drug for the treatment of arrhythmia and arterial hypertension is becoming increasingly widespread in experimental and clinical practice. This method, thanks to the mathematical analysis of the time and frequency characteristics of heart rate variability, allows you to get an idea of slow oscillatory processes that constantly exist in the body and have the properties of autowaves. The use of this method gives an idea of the role of various departments of the autonomic nervous system (sympathetic and parasympathetic), as well as the implementation of humoral mechanisms in the implementation of the chronotropic function of the heart.

Abstract 17599: Sotatercept for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review and Single-Arm Meta-Analysis

Introduction: Pulmonary arterial hypertension (PAH) is associated with progressive clinical worsening and a 50% 5-year survival rate with current PAH therapies. Sotatercept is a first-in-class fusion protein with promising results in preclinical trials, but clinical evidence on its role in treating PAH remains limited. Hypothesis: Sotatercept may provide clinical benefits for patients with symptomatic PAH. Aims: To assess the efficacy of sotatercept in addition to background PAH therapy in this population. Methods: We searched PubMed, Embase, Cochrane and Clinicaltrials.gov in April 2023 for clinical trials assessing efficacy outcomes of sotatercept in patients with PAH. Using a random-effects model, we performed a single-arm meta-analysis of proportions for binary outcomes and applied generic inverse variance weighting formulas to pool arithmetic means and least squares means for continuous outcomes. Statistical analyses were performed using Review Manager 5.4.1 and R software 4.2.2. Results: We included three clinical trials comprising 254 patients with WHO functional class II or III PAH. At 24 weeks, only 2% of patients on sotatercept experienced symptoms of clinical worsening (95% CI 1 to 5; Fig. 1A). Sotatercept was also associated with a reduction in pulmonary vascular resistance (mean change from baseline -199.92 dyn·sec·cm -5 ; 95% CI -256.83 to -143.0; Fig. 1B), while improving 6-minute walk distance (mean change from baseline 45.86 m; 95% CI 28.54 to 63.18; Fig. 1C). Conclusions: These findings suggest that sotatercept may improve exercise capacity while decelerating clinical worsening and attenuating pulmonary vascular resistance in patients with mild to moderate PAH.

Abstract 14923: Induced Pluripotent Stem Cell Derived Endothelial Progenitor Cells Attenuate Pulmonary Arterial Hypertension

Introduction: Although transplantation of adult endothelial progenitor cells (EPCs) holds promise in the treatment for pulmonary arterial hypertension (PAH), the low number and weakened functions of human primary EPCs are serious problems for autologous transplantation for patients and limited their therapeutic efficiency. Hypothesis: Te aim of this study is to investigate the efficiency of induced pluripotent stem cell derived EPCs on attenuating PAH. Methods: This study differentiated induced pluripotent stem cells from healthy people into vascular endothelial precursor cells (iPSC-EPC), whose specific protein expressed CD133 accounted for 95.4% and KDR accounted for 75.7%, and further confirmed that iPSC-EPC have the ability to differentiate vascular endothelial cells (iPSC-EC) with similar EC cobblestone morphology, acetylated LDL uptake, and UEA-1 lectin binding. IPSC-EC-specific protein expression CD144 accounts for 99.0% and CD31 accounts for 75.1%. Results: This study explored the efficacy of healthy iPSC-EPC in the treatment of PAH in an animal model. Both prophylactic and therapeutic treatments of iPSC-EPC were effective in rescuing monocrotaline (MCT)-induced right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary artery wall thickening in PAH. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-EPC derived culture medium (EPC-CM) treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by EPC-CM with suppression of PCNA, cyclin D1, MMP-1, and MMP-9. This study also found that iPSC-EPC treatment reduced MCT-PASMC senescence and senescence-associated secretory phenotype (SASP) in MCT-treated rats. Conclusions: This study found that ctrl iPSC-EPC restored miRNA levels in the lung tissue of MCT-treated rats. IPSC-EPC is effective at preventing and reversing pulmonary hypertension by regulating the expression of miRNAs, and reducing pulmonary vascular remodelling.

Abstract 13431: Safety and Efficacy of Pulmonary Artery Denervation Therapy for the Treatment of Pulmonary Artery Hypertension

Background: Despite recent advances in the treatment of pulmonary arterial hypertension (PAH), the survival rate remains poor in severe PAH. Pulmonary artery denervation (PADN) therapy for PAH is gaining popularity, although the safety and efficacy of PADN were not fully evaluated. Therefore, we conducted an updated systematic review and meta-analysis of the safety and efficacy of PADN in the treatment of patients with PAH. Methods: Using PRISMA guidelines, we searched PubMed, Embase, Cochrane, and the Clinical Trials.gov databases from inception till May 2023 for placebo-controlled outcome studies that compared PADN therapy to placebo in patients with moderate-severe PAH. The literature was screened for appropriate randomized clinical trials (RCT) and prospective studies, and data were extracted and analyzed. Comprehensive meta-analysis software (CMA v3, Biostat Inc. Englewood, NJ, USA) was utilized to perform statistical analyses. Results: The metanalysis included 8 studies (7 RCTs and 1 prospective) with 577 patients (PADN group = 270, placebo = 307). PADN treatment was associated with a significant reduction in mean pulmonary artery pressure [weighted mean difference (WMD) = -6.9 mmHg; 95% CI = -9.7, -4.1; P &lt; 0.01; I 2 = 61] and pulmonary vascular resistance [WMD = -3.2 dyne.s.cm -5 ; 95% CI = -5.4, -0.9; P = 0.005; I 2 = 95]. There was a statistically significant improvement in the cardiac output [WMD = 0.3 l/min; 95% CI = 0.07, 0.6; P=0.012; I 2 = 76] and numerical improvement in 6-minute walking distance [WMD = 67.7m; 95% CI = -3.73, 139.2; P = 0.06; I 2 = 95] in the PADN group. There were fewer side effects in the PADN group as compared to the placebo group. Conclusion: This updated metanalysis supports PADN as a safe and efficacious therapy for moderate-severe PAH. Findings are limited by small sample size, medium-quality literature, and large data heterogeneity, necessitating larger RCT with clinical endpoints comparing PADN therapy with optimal medical treatment.

Updating approaches to patient management in the light of new European guidelines on arterial hypertension: analytical review

Data from epidemiological studies show a high prevalence of cardiovascular diseases, including arterial hypertension (AH) and the risk of complications, with changes in AH control and treatment techniques. The review article summarizes the main directions of the new European guidelines on hypertension, which help implement different patient groups in outpatient practice. Secondary risk factors for cardiovascular disease are revised in the new clinical guidelines. The recommendation outlines a diagnostic and therapeutic approach for resistant arterial hypertension, its associated phenotypes, and night-time hypertension. The use and position of renal denervation for antihypertensive treatment have been updated compared with previous recommendations. The new European clinical guidelines reflect a differentiated approach to target indicators of ambulatory blood pressure in different age groups, with functional levels of aging, comorbidity, and AH phenotypes, which is of great clinical importance for a primary care physician and can significantly reduce the risk of heart disease vascular complications.

Sartans in the treatment of arterial hypertension: focus on telmisartan and azilsartan. A review

The activity of the renin-angiotensin-aldosterone system is one of the main pathogenetic mechanisms underlying cardiovascular diseases at all stages of the cardiovascular continuum. This article discusses the role of telmisartan and azilsartan as the most powerful sartans in modern cardiology. Azilsartan and especially telmisartan have a significant organoprotection and are superior to other antihypertensive drugs in terms of lowering blood pressure. However, the effect of azilsartan on hard endpoints has not been studied while the efficacy of telmisartan on hard endpoints has been evaluated in plenty clinical trials including 3 large randomized clinical trials with several thousand patients. The article also presents calculations showing the better cost-effectiveness of telmisartan compared to azilsartan.

Сardioprotective agents with biaromatic structure. Part 6. Beta blockers

β-Blockers are one of the oldest classes of cardioprotectors used in the treatment of cardiovascular diseases. They reduce the heart rate, have a hypotensive effect, inhibit myocardial contractility and have antiarrhythmic properties. In the series of biaromatic compounds with a linear linker, there is a quite large group of β-blockers, which in addition to two aromatic nuclei contain a 1,2-dihydroxy-3-aminopropane fragment in the linker, that is the key for the presence of β-blocking activity. Among the compounds of this group are widely used drugs nebivolol and carvedilol, which are used in the treatment of chronic heart failure and arterial hypertension.

Targeting IL-11 system as a treatment of pulmonary arterial hypertension

IL-11 is linked to fibrotic diseases, but its role in pulmonary hypertension is unclear. We examined IL-11's involvement in idiopathic pulmonary arterial hypertension (iPAH). Using samples from control (n = 20) and iPAH (n = 6) subjects, we assessed IL-11 and IL-11Rα expression and localization through RT-qPCR, ELISA, immunohistochemistry, and immunofluorescence. A monocrotaline-induced PAH model helped evaluate the impact of siRNA-IL-11 on pulmonary artery remodeling and PH. The effects of recombinant human IL-11 and IL-11Rα on human pulmonary artery smooth muscle cell (HPASMC) proliferation, pulmonary artery endothelial cell (HPAEC) mesenchymal transition, monocyte interactions, endothelial tube formation, and precision cut lung slice (PCLS) pulmonary artery remodeling and contraction were evaluated. IL-11 and IL-11Rα were over-expressed in pulmonary arteries (3.2-fold and 75-fold respectively) and serum (1.5-fold and 2-fold respectively) of patients with iPAH. Therapeutic transient transfection with siRNA targeting IL-11 resulted in a significant reduction in pulmonary artery remodeling (by 98%), right heart hypertrophy (by 66%), and pulmonary hypertension (by 58%) in rats exposed to monocrotaline treatment. rhIL-11 and soluble rhIL-11Rα induce HPASMC proliferation and HPAEC to monocyte interactions, mesenchymal transition, and tube formation. Neutralizing monoclonal IL-11 and IL-11Rα antibodies inhibited TGFβ1 and EDN-1 induced HPAEC to mesenchymal transition and HPASMC proliferation. In 3D PCLS, rhIL-11 and soluble rhIL-11Rα do not promote pulmonary artery contraction but sensitize PCLS pulmonary artery contraction induced by EDN-1.In summary, IL-11 and IL-11Rα are more highly expressed in the pulmonary arteries of iPAH patients and contribute to pulmonary artery remodeling and the development of PH.

Viewpoint: activin signalling inhibitors for the treatment of pulmonary arterial hypertension

Viewpoint: activin signalling inhibitors for the treatment of pulmonary arterial hypertension

A Network Meta-analysis of the Efficacy and Safety of Targeted Drug Combinations in the Treatment of Pulmonary Arterial Hypertension

Objective: This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension (PAH). Methods: Searches were conducted in Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1, 2022. The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. A network meta-analysis was performed using Stata 16.0 software. The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot, funnel plot, and surface under the cumulative ranking. Results: A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study. The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy. Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels. Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure, whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance. Bosentan in combination with tadalafil significantly improved the Borg dyspnea score, and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class. In terms of safety, there was no significant reduction in the incidence of adverse events, hospitalizations, or all-cause mortality for combination therapy compared with monotherapy. Bosentan combined with sildenafil significantly reduced the risk of serious adverse events, but the risk of discontinuation due to an adverse event was higher than monotherapy. Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH. Conclusion: Compared with monotherapy, targeted drug combinations for PAH significantly improves exercise tolerance, pulmonary hemodynamic parameters, and reduces the risk of serious adverse events and clinical worsening in patients. Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH. Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.

Impact of Parenteral Prostanoids in Pulmonary Arterial Hypertension: The Relevance of Timing.

Parenteral prostanoids are being recommended in pulmonary arterial hypertension (PAH) treatment, but the prognostic relevance of delayed treatment initiation is still debated. This study assessed the impact of the timing of prostacyclin treatment initiation on reducing PVR and achieving a low-risk profile in PAH patients. The study enrolled 151 patients who started on parenteral prostanoids with different treatment strategies. All patients underwent right heart catheterization, clinical evaluation, and risk assessments at baseline and after 1-year follow-up. Patients with an upfront strategy including parenteral prostanoid plus one oral drug had -5.3 ± 6.2 WU (-50 ± 19%) reduction in PVR, patients with an upfront strategy including parenteral prostanoid plus double oral drug had -12.8 ± 5.9 WU (-68 ± 17%) reduction in PVR, while patients with an add-on strategy including parenteral prostanoid after oral drugs had -3.9 ± 3.5 WU (-23 ± 19%) reduction in PVR. An upfront strategy including parenteral prostanoids was independently associated with an increased likelihood of achieving the greater reduction of PVR compared with an add-on strategy. Additionally, the greater the severity of PH at the time of diagnosis, in terms of PVR and RV reverse remodeling, the higher the probability of treatment failure. An upfront strategy including a parenteral prostanoid is associated with the highest likelihood of achieving a low-risk profile and a greater reduction of PVR compared with parenteral prostanoid as an add-on to oral treatment.